(1) Field of the Invention
This invention relates to a method of increasing high density lipoprotein (HDL)-cholesterol levels in serum. In particular it relates to methods of increasing serum HDL-cholesterol levels by use of certain phenylethylamine derivatives.
(2) Description of the Prior Art
Coronary artery disease (CAD) in the United States accounts for 650,000 deaths annually at a cost of over $28.5 billion per year (American Heart Association Heart Facts. 1978, Dallas). It is the most common cause of death in this country. Over the years considerable research effort has been directed at finding factors which alter CAD risk. Factors associated with increased risk of CAD include smoking, hypertension, obesity, hyperlipidemia, inactivity, diet, being male, and genetic factors. On the other hand alcohol consumption, exercise, thinness, being female, and genetic predisposition are factors associated with decreased risk of CAD.
Much effort has been made to correct CAD risk factors including weight reduction, hypertension control, exercise, low cholesterol and saturated fat diet, smoking reduction, and lipid reducing agents. Lipid lowering products have been used in hyperlipoproteinemias in order to arrest, reverse, or prevent atherosclerosis. Typical of such substances are lecithin, pectin, cottonseed oil, and the mucilaginous substances listed in U.S. Pat. No. 3,148,114. In addition, several synthetic hypolipidemic agents are now available, namely, clofibrate, D-thyrozine, cholestyramine, and nicotinic acid [(Levy & Frederickson, Postgraduate Medicine 47, 130 (1970)].
Other useful hypolipidemic agents disclosed in the prior art and N,N'-disubstituted-p-phenylenediamines (U.S. Pat. No. 3,819,708) -.alpha.tertiary butyl-p-phenoxybenzlyamines (U.S. Pat. No. 3,946,119) and bis-substituted benzyl methanamines (U.S. Pat. No. 4,035,508).
If a drug could be found which increased HDL concentration, then ingestion of this substance might reduce the risk of CAD. Alcohol consumption has the above properties, however, its abuse potential and toxicity limit its practical usefulness.
High density lipoprotein (HDL)-cholesterol concentration has been found to be the best serum predictor of coronary artery disease (CAD). High levels of HDL are associated with a low risk of CAD and low levels with a high risk of CAD. High density lipoprotein appears to be the cholesterol "scavenger" of the body--it removes cholesterol from cells and carries it to the liver for excretion. Since factors which are associated with protection from coronary artery disease (exercise, alcohol consumption, estrogen, thinness, genetics) are associated with high HLD-cholesterol levels, it has been proposed that elevated serum HDL may bring about the protection. In fact, HDL has been called the "antiatherogenic lipoprotein".
Recent reports have revealed that four Beta-adrenergic blockers (propranolol, metoprolol, atenolol, sotalol) lower HDL levels. Hooper, P. L.: Effect of Propranolol on Plasma Concentrations of HDL Apoproteins and Lipids. Br. Med. J. 6157:200, Jan. 1979; Bielmann, P. & Leduc, G.: Effects of Metoprolol and Propranolol on Lipid Metabolism. Int. J. Clin. Pharmacol Biopharm. 17:378-382, 1979. England, J. D. F.: et al. The Effect of Metoprolol and Atenolol on Plasma HDL Levels in Man. Clin. Exp. Pharmacol. Physiol. 7:329-33, 1980. Lehtonen, A.: Long-Term Effect of Sotalol on Plasma Lipids. Clin. Sci. 57:Suppl. 5:405.sub.s -7.sub.s, 1979.